Hemodynamic overload of the left ventricle results in LV remodeling with the development of myocardial hypertrophy that often progresses to failure. In patients with heart failure there is increased oxidative stress suggesting that reactive oxygen species (ROS) may be involved. Using an in vitro system of cyclic mechanical strain that simulates the higher wall stress that occurs with hemodynamic overload, I have shown ROS plays a critical role in mediating two key features of myocardial remodeling-myocyte growth and apoptosis. The ROS that mediate these effects of mechanical strain on cardiocyte phenotype is unknown. Several lines of evidence suggest that hydrogen peroxide (H2O2) plays a central role. First, my preliminary data obtained by overexpressing superoxide dismutase and catalase in cardiac myocytes in vitro suggests that H2O2, not superoxide, mediates both myocyte growth and apoptosis. Second, other data confirm that direct application of H2O2 can cause both growth and apoptosis of cardiac myocytes in vitro. Finally, higher levels of hydroxyl radical (.OH), a breakdown product of H2O2, have been demonstrated in failing heart. Thus, my primary hypothesis is that H2O2 plays a major role in mediating myocardial remodeling due to hemodynamic overload. The goals of this project are: 1) to define the role of hydrogen peroxide in mechanical stretch-induced myocyte growth and apoptosis; 2) to determine the signaling kinases that are activated by hydrogen peroxide and the direct redox modifications that occur with these; 3) to utilize in vivo mouse models of site directed mitochondrial catalase to evaluate the short and chronic effects of pressure overload and the benefits of antioxidants; and 4) the use of proteomics to evaluate the direct protein modifications that may regulate protein function.